8-89953700-TAAAA-TAAA

Variant names:

• chr8-89953700-TA-T
• rs587780555
• NM_002485.5:c.1398-10delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_002485.5(NBN):​c.1398-10delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,578,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.25
• Publications: 1 publications found

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 8-89953700-TA-T is Benign according to our data. Variant chr8-89953700-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 530780.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.1398-10delT		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1152-10delT		intron	N/A	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1152-10delT		intron	N/A	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.1398-10delT		intron	N/A	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.1398-10delT		intron	N/A	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.1398-10delT		intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes AF: 0.0000265 AC: 4 AN: 150902 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.000193

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000603 AC: 123 AN: 203826 AF XY: 0.000667

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.000459

Gnomad ASJ exome AF: 0.000114

Gnomad EAS exome AF: 0.000320

Gnomad FIN exome AF: 0.00135

Gnomad NFE exome AF: 0.000540

Gnomad OTH exome AF: 0.000402

GnomAD4 exome AF: 0.000184 AC: 263 AN: 1427734 Hom.: 0 Cov.: 30 AF XY: 0.000189 AC XY: 134 AN XY: 710342

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000246 AC: 8 AN: 32504

American (AMR) AF: 0.000446 AC: 19 AN: 42576

Ashkenazi Jewish (ASJ) AF: 0.0000392 AC: 1 AN: 25506

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39154

South Asian (SAS) AF: 0.000347 AC: 29 AN: 83672

European-Finnish (FIN) AF: 0.000750 AC: 37 AN: 49332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5320

European-Non Finnish (NFE) AF: 0.000149 AC: 163 AN: 1090680

Other (OTH) AF: 0.0000848 AC: 5 AN: 58990

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000265 AC: 4 AN: 150902 Hom.: 0 Cov.: 32 AF XY: 0.0000272 AC XY: 2 AN XY: 73638

African (AFR) AF: 0.00 AC: 0 AN: 41112

American (AMR) AF: 0.0000662 AC: 1 AN: 15108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4790

European-Finnish (FIN) AF: 0.000193 AC: 2 AN: 10336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67628

Other (OTH) AF: 0.00 AC: 0 AN: 2072

Alfa AF: 0.00170 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780555; hg19: chr8-90965928; COSMIC: COSV55372021; COSMIC: COSV55372021;